Pulmonary infection by SARS-CoV-2 induces senescence accompanied by an inflammatory phenotype in severe COVID-19: possible implications for viral mutagenesis.

Autor:	Evangelou K; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Contributed equally., Veroutis D; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Biomedical Research Foundation, Academy of Athens, Athens, Greece.; Contributed equally., Paschalaki K; National Heart and Lung Institute, Imperial College London, London, UK.; Contributed equally., Foukas PG; 2nd Dept of Pathology, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Lagopati N; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Biomedical Research Foundation, Academy of Athens, Athens, Greece., Dimitriou M; 2nd Dept of Pathology, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Laboratory of Biology, Dept of Medicine, Democritus University of Thrace, Alexandroupolis, Greece., Papaspyropoulos A; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Biomedical Research Foundation, Academy of Athens, Athens, Greece., Konda B; Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Hazapis O; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Polyzou A; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Havaki S; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Kotsinas A; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Kittas C; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK., Tzioufas AG; Dept of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., de Leval L; Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland., Vassilakos D; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Tsiodras S; 4th Dept of Internal Medicine, Attikon University Hospital, University of Athens Medical School, Athens, Greece.; Hellenic Centre for Disease Control and Prevention, Athens, Greece., Stripp BR; Lung and Regenerative Medicine Institutes, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Papantonis A; Translational Epigenetics Group, Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.; Center for Molecular Medicine, University of Cologne, Cologne, Germany., Blandino G; Oncogenomic and Epigenetic Unit, IRCCS, Regina Elena National Cancer Institute, Rome, Italy., Karakasiliotis I; Laboratory of Biology, Dept of Medicine, Democritus University of Thrace, Alexandroupolis, Greece., Barnes PJ; National Heart and Lung Institute, Imperial College London, London, UK.; P.J. Barnes and V.G. Gorgoulis contributed equally to this article as lead authors and supervised the work., Gorgoulis VG; Molecular Carcinogenesis Group, Dept of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece vgorg@med.uoa.gr.; Biomedical Research Foundation, Academy of Athens, Athens, Greece.; Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.; Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.; Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; P.J. Barnes and V.G. Gorgoulis contributed equally to this article as lead authors and supervised the work.
Jazyk:	angličtina
Zdroj:	The European respiratory journal [Eur Respir J] 2022 Aug 18; Vol. 60 (2). Date of Electronic Publication: 2022 Aug 18 (Print Publication: 2022).
DOI:	10.1183/13993003.02951-2021
Abstrakt:	Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the respiratory system can progress to a multisystemic disease with aberrant inflammatory response. Cellular senescence promotes chronic inflammation, named senescence-associated secretory phenotype (SASP). We investigated whether coronavirus disease 2019 (COVID-19) is associated with cellular senescence and SASP. Methods: Autopsy lung tissue samples from 11 COVID-19 patients and 43 age-matched non-COVID-19 controls with similar comorbidities were analysed by immunohistochemistry for SARS-CoV-2, markers of senescence and key SASP cytokines. Virally induced senescence was functionally recapitulated in vitro , by infecting epithelial Vero-E6 cells and a three-dimensional alveosphere system of alveolar type 2 (AT2) cells with SARS-CoV-2 strains isolated from COVID-19 patients. Results: SARS-CoV-2 was detected by immunocytochemistry and electron microscopy predominantly in AT2 cells. Infected AT2 cells expressed angiotensin-converting enzyme 2 and exhibited increased senescence (p16 INK4A and SenTraGor positivity) and interleukin (IL)-1β and IL-6 expression. In vitro , infection of Vero-E6 cells with SARS-CoV-2 induced senescence (SenTraGor), DNA damage (γ-H2AX) and increased cytokine (IL-1β, IL-6, CXCL8) and apolipoprotein B mRNA-editing (APOBEC) enzyme expression. Next-generation sequencing analysis of progenies obtained from infected/senescent Vero-E6 cells demonstrated APOBEC-mediated SARS-CoV-2 mutations. Dissemination of the SARS-CoV-2-infection and senescence was confirmed in extrapulmonary sites (kidney and liver) of a COVID-19 patient. Conclusions: We demonstrate that in severe COVID-19, AT2 cells infected by SARS-CoV-2 exhibit senescence and a proinflammatory phenotype. In vitro , SARS-CoV-2 infection induces senescence and inflammation. Importantly, infected senescent cells may act as a source of SARS-CoV-2 mutagenesis mediated by APOBEC enzymes. Therefore, SARS-CoV-2-induced senescence may be an important molecular mechanism of severe COVID-19, disease persistence and mutagenesis. Competing Interests: Conflict of interest: P.J. Barnes receives research funding from AstraZeneca and Boehringer Ingelheim and is a scientific advisor to AstraZeneca, Boehringer Ingelheim, Epi-Endo, Novartis, Pieris and Teva. The other authors wish to declare no conflict of interest. (Copyright ©The authors 2022.)
Databáze:	MEDLINE
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